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Abstract

Leptin has been shown to affect energy homeostasis, learning and memory, and some models of anxiolytic action. However, leptin has produced inconsistent results in previous non-operant behavioural tests of anxiety. Here, we test the anxiolytic potential of leptin in an operant paradigm that has produced positive results across all classes of anxiolytic so far tested. Rats were tested in the Fixed Interval 60 Seconds (FI60) task following administration of 0/0.5/1.0mg/kg (i.p.) leptin or an active anxiolytic control of 5 mg/kg (i.p.) chlordiazepoxide (CDP). By the end of the 14 days of testing in the FI60 task, 0.5mg/kg leptin released suppressed responding in a manner similar to CDP, and 1.0mg/kg leptin produced a relative depression in responding, a similar outcome pattern to previously tested 5HT-agonist anxiolytics. This suggests that leptin behaves similarly to established serotonergic anxiolytics such as buspirone and fluoxetine; with the delay in development of effect during testing, and the inverted-U dose-response curve explaining the inconsistent behaviour of leptin in behavioural tests of anxiety, as this type of pattern is common to serotonergic anxiolytics.

The frequency of hippocampal theta rhythm is modulated on a circadian period and is entrained by food availabilityFRONTIERS IN BEHAVIORAL NEUROSCIENCEMunn, R. G., Tyree, S. M., McNaughton, N., Bilkey, D. K.2015; 9

Abstract

The hippocampal formation plays a critical role in the generation of episodic memory. While the encoding of the spatial and contextual components of memory have been extensively studied, how the hippocampus encodes temporal information, especially at long time intervals, is less well understood. The activity of place cells in hippocampus has previously been shown to be modulated at a circadian time-scale, entrained by a behavioral stimulus, but not entrained by light. The experimental procedures used in the previous study of this phenomenon, however, necessarily conflated two alternative entraining stimuli, the exposure to the recording environment and the availability of food, making it impossible to distinguish between these possibilities. Here we demonstrate that the frequency of theta-band hippocampal EEG varies with a circadian period in freely moving animals and that this periodicity mirrors changes in the firing rate of hippocampal neurons. Theta activity serves, therefore, as a proxy of circadian-modulated hippocampal neuronal activity. We then demonstrate that the frequency of hippocampal theta driven by stimulation of the reticular formation also varies with a circadian period. Because this effect can be observed without having to feed the animal to encourage movement we were able to identify what stimulus entrains the circadian oscillation. We show that with reticular-activated recordings started at various times of the day the frequency of theta varies quasi-sinusoidally with a 25 h period and phase-aligned when referenced to the animal's regular feeding time, but not the recording start time. Furthermore, we show that theta frequency consistently varied with a circadian period when the data obtained from repeated recordings started at various times of the day were referenced to the start of food availability in the recording chamber. This pattern did not occur when data were referenced to the start of the recording session or to the actual time of day when this was not also related to feeding time. This double dissociation demonstrates that hippocampal theta is modulated with a circadian timescale, and that this modulation is strongly entrained by food. One interpretation of this finding is that the hippocampus is responsive to a food entrainable oscillator (FEO) that might modulate foraging behavior over circadian periods.

Abstract

The accurate recall of an event is usually dependent on a memory trace that encodes three pieces of information; what happened, when the event happened, and where. The established phenomenology of hippocampal CA1 pyramidal neurons could reflect mechanisms via which some of this information (where and what) is encoded; but so far there has been little evidence for a mechanism by which these cells might represent "when." It was therefore of interest to examine the activity of CA1 neurons over a substantial temporal duration. Forty-eight CA1 neurons were recorded once an hour during long (24-48 h) exposures to a single, stable environment where minimal time-of-day cues were available. Only data from the first 25 h of recording was analyzed quantitatively. We found that the mean ensemble firing rate of these cells changed predictably such that it was closely correlated (r = 0.707) to a reference sine wave with a 25-h period and a positive peak at recording start. This relationship was not explained by changes in the animal's running speed or amount of the recording environment covered in each recording session. When data were referenced to the onset or offset of the normal light-on period, the correlation with the sinusoid was abolished. At an individual cell level, the majority of neurons (n = 31) had significant correlations (P < 0.05) with the reference sine. We conclude that the firing rate of a large proportion of cells in area CA1 of the hippocampus are modulated over a circadian period but that this modulation is not entrained to light. Rather, entry into the environment and the associated food availability appear to be the entraining factors. We hypothesize that these neurons may be part of the putative food-entrainable oscillator. Such a system could enable an animal to discriminate between spatial representations on a temporal dimension with reference to the time of food availability.

Abstract

Anxiolytics that act as GABAA agonists and those that act as 5-HT1A receptor agonists all reduce the frequency of hippocampal rhythmic slow activity (RSA). Changes in RSA have been linked to changes in behavioural inhibition and therefore anxiety - but this has not been tested with specific serotonin reuptake inhibitors, which are antidepressant and anxiolytic; therefore we tested the effects of fluoxetine on RSA and behavioural inhibition. Fluoxetine (FLU; 10 and 20 mg/kg, intraperitoneally) produced a dose-related reduction in the frequency of reticular-elicited RSA. Groups of rats received, intraperitoneally, either (i) saline, or 5 mg/kg fluoxetine, or 10 mg/kg fluoxetine; or (ii) saline, or 20 mg/kg fluoxetine, or 6.6 mg/kg of the 5-HT1A agonist buspirone (BUS) and were tested on a fixed interval 60-s schedule and a differential reinforcement of low rates 15-s schedule. FLU at 5 mg/kg produced effects similar to low doses of BUS and other anxiolytics. FLU (10 and 20 mg/kg) produced effects more like those reported earlier for higher doses of BUS. These results continue to link anxiolysis, RSA and behavioural inhibition, and suggest that serotonergic anxiolytics share some of the central actions of GABAergic anxiolytics, but at higher doses, administered acutely, have distinct side effects that can obscure their anxiolytic action in behavioural tasks.